# FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies

## TL;DR

This paper reviews FGFR2-related biliary tract cancer, focusing on biology, resistance to treatments, and new strategies to improve patient outcomes.

## Contribution

The paper provides a comprehensive overview of FGFR2 alterations in biliary tract cancer and emerging strategies to overcome treatment resistance.

## Key findings

- FGFR2 rearrangements are actionable targets in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma.
- Acquired resistance to FGFR inhibitors is often driven by secondary mutations and bypass signaling pathways.
- Next-generation inhibitors and combination therapies are being explored to overcome resistance and improve treatment outcomes.

## Abstract

Biliary tract cancer is a rare and aggressive cancer with limited treatment options and poor survival outcomes. In recent years, alterations in fibroblast growth factor receptor 2 (FGFR2) have been identified in a subset of patients, particularly those with intrahepatic cholangiocarcinoma. These genetic changes drive tumor growth but also create an opportunity for targeted treatment. Several drugs that inhibit FGFR2 have shown meaningful clinical benefit; however, most patients eventually develop resistance, leading to disease progression. This review summarizes current knowledge of FGFR2-related cancer biology, available targeted therapies, and the main mechanisms by which resistance develops. We also discuss emerging treatment strategies, including next-generation drugs, combination approaches, and the use of blood-based testing to monitor disease evolution. Improving understanding of these mechanisms may help guide future treatment decisions and improve outcomes for patients with FGFR2-altered biliary tract cancer.

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to FGFR-targeted therapies. Selective FGFR tyrosine kinase inhibitors, including the reversible inhibitor pemigatinib and the irreversible inhibitor futibatinib, have demonstrated clinically meaningful response rates and durable disease control in patients with previously treated FGFR2-altered iCCA, leading to regulatory approvals and the incorporation of FGFR inhibition into contemporary treatment paradigms. However, the development of acquired resistance—most commonly driven by secondary kinase-domain mutations and activation of bypass signaling pathways—remains a major limitation to sustained therapeutic benefit. This review summarizes the biological basis of FGFR2 alterations, highlights current clinical evidence supporting FGFR inhibition, and discusses the evolving landscape of resistance mechanisms. We further examine emerging therapeutic strategies aimed at overcoming resistance, including next-generation FGFR inhibitors and rational combination approaches. In addition, we highlight the growing role of circulating tumor DNA as a noninvasive tool for longitudinal molecular monitoring and treatment guidance. Together, these insights underscore the central role of FGFR2-directed therapy in precision oncology for biliary tract cancer and provide a framework for optimizing and extending targeted treatment in this molecularly defined disease subset.